AbstractBACKGROUND: SLC25A13 gene mutations cause citrin deficiency, which leads to neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Information on the mutation spectrum of SLC25A13 in the Chinese population is limited. The aim of this study was to explore the mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and various forms of aminoacidemia.

METHODS: Sequence analyses were performed on 39 infants with intrahepatic cholestasis and various forms of aminoacidemia. Novel mutations were subjected to homology and structural analyses. Western blots were performed when liver specimens available.

CONCLUSIONS: The mutation spectrum of the SLC25A13 gene in a Chinese population of infants with intrahepatic cholestasis with various forms of aminoacidemia was found to be different from that of other population groups in East Asia. The SLC25A13 gene mutation is the most important cause of infantile intrahepatic cholestasis with various forms of aminoacidemia.

Public Health Preparedness Heart-lung machine may be considered for certain patients with H1N1 influenza with acute respiratory failure

Many young adults who contracted the novel 2009 influenza H1N1 virus were admitted to intensive care units with severe respiratory failure. A review of studies comparing different methods of getting oxygen into the lungs of such patients suggests that clinicians should consider extracorporeal membrane oxygenation (ECMO) along with other salvage therapies in patients failing conventional therapy. ECMO has been used for respiratory failure in different types of patients, but there are no clinical guidelines for its use in patients with the flu.

In this review of studies, the researchers found no randomized controlled trials of ECMO in flu patients. They did find an observational study of H1N1 flu patients in Australia and New Zealand that reported on 68 patients treated with ECMO, which uses a modified heart-lung machine (a mechanical pump to oxygenate and circulate the patient's blood), and 133 treated with mechanical ventilation (via a breathing tube) during winter in those countries. However, the two groups were not comparable because one group had more severe lung damage than the other.

To get additional information, the researchers combined the findings from three randomized trials of ECMO therapy conducted over 30 years, regardless of the origin of respiratory distress. This meta-analysis found a suggestive, but not statistically significant, reduction in deaths compared with patients not receiving ECMO. A more recent study randomly assigned 90 patients to ECMO therapy and 90 to conventional management (control group). The risk of death or severe disability at 6 months was a significant 31 percent less for the ECMO than the control group. However, the risk of death by 6 months just missed statistical significance. The study was funded in part by the Agency for Healthcare Research and Quality (HS18406).

More details are in "A systematic review to inform institutional decisions about the use of extracorporeal membrane oxygenation during the H1N1 influenza pandemic," by Matthew D. Mitchell, Ph.D., Mark E. Mikkelsen, M.D., M.S.C.E., Ingi Lee, M.D., M.S.C.E., and others in the June 2010 Critical Care Medicine 38(6), pp. 1398-1404.

Human growth hormone can be used successfully to treat some symptoms of cystic fibrosis, but its impact on the disease itself remains unknown, according to a new report funded by the Agency for Healthcare Research and Quality (AHRQ). Cystic fibrosis is an inherited chronic multi-organ disease, caused by a defective gene, in which the body produces thick mucus that clogs the lungs and leads to life-threatening lung infections. The disease also makes it difficult for the pancreas to work, hampering the ability to absorb food. Common signs are salty tasting skin, difficulty breathing, chronic lung infections, poor weight gain, and shorter height. The disease typically is detected in childhood, stunting the patient's growth and usually leading to early death.

The report, Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of Patients with Cystic Fibrosis, finds that the use of human growth hormone increases height and weight, may improve lung functioning, and may strengthen the bones of patients with cystic fibrosis. Researchers found evidence suggesting that human growth hormone therapy reduces the need for hospitalizations, but could find no evidence that the therapy prolongs life or improves health-related quality of life. The use of human growth hormone was also found to raise blood sugar, which over time may lead to the development of diabetes in some patients.

"Patients with cystic fibrosis and their families have long looked for ways to manage this disease," said AHRQ Director Carolyn M. Clancy, M.D. "This report gives patients and their families excellent information that they can use, in consultation with their doctors, to make decisions about care."

The report was produced by the University of Connecticut/Hartford Hospital Evidence-based Practice Center for AHRQ. Results of the report were published online in the October issue of Pediatrics. Researchers examined published evidence from 53 unique studies of the effect of human growth hormone in cystic fibrosis patients as well as patients who did not have cystic fibrosis.

Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of Patients with Cystic Fibrosis is the newest comparative effectiveness review from AHRQ's Effective Health Care Program. The Effective Health Care Program represents a leading Federal effort to compare alternative treatments for health conditions and make the findings public to help doctors, nurses, pharmacists, and others work together with patients to choose the most effective treatments.

In conjunction with the new report, AHRQ will soon publish plain-language summary guides about human growth hormone in cystic fibrosis for patients, clinicians, and policymakers. Summary guides on numerous clinical topics and other information and background on the Effective Health Care Program can be found at http://www.effectivehealthcare.ahrq.gov.

Women's Health One-fifth of mothers do not receive recommended antenatal corticosteroids before delivery of premature infants

Strong evidence demonstrates that antenatal corticosteroids during preterm labor reduce the incidence of respiratory distress syndrome and other secondary complications associated with prematurity. Yet, 20 percent of eligible mothers failed to receive indicated antenatal corticosteroid therapy, according to a study at three New York City hospitals. Of these women, 43 percent delivered more than 2 hours after admission and 33 percent delivered more than 4 hours after admission, indicating sufficient time to have treated them.

The failure to administer recommended steroids was related strongly to how long after admission the delivery took place. Seventy-nine women delivered within 2 hours of admission and 73 percent of them did not receive the therapy. By contrast, only 8 percent of those who delivered between six and eight hours after admission did not receive recommended corticosteroids. This may be because the National Institutes of Health (NIH) Consensus Statement (1994) supporting the use of antenatal corticosteroids excludes from its recommendation women for whom immediate delivery was anticipated. Many of the women who delivered within 2 hours of admission were probably expected to deliver immediately, note the researchers.

In this study, women whose cervixes were at a more advanced stage were also less likely to receive steroids, suggesting that physicians chose to withhold steroids from women for whom they anticipated immediate delivery. They were generally correct (if imprecise), but wrong one-third of the time, note the researchers. They state that incorporating a physician's capacity to predict the immediate future regarding the time of delivery may have inadvertently subverted the capacity of the NIH guideline to guide practice. They recommend that the NIH guideline may have been more effectively implemented had the statement suggested that steroids should be provided to all eligible women who do not deliver within a specific time period, such as 1 hour after admission. The other factors associated with failure to receive recommended therapy were lack of prenatal care, longer gestation, advanced cervical exam, and intact membranes at admission.

The study included 515 women eligible for antenatal corticosteroids, of whom 70 percent were black or Hispanic. Most were insured through Medicaid or a Medicaid HMO. This study was supported, in part, by the Agency for Healthcare Research and Quality (HS10859).

Outcomes/Effectiveness Research Higher risk of death or heart attack in first 90 days after cardiac patients stop taking clopidogrel

Earlier studies suggest that cardiac patients may experience problems after they stop taking the blood-thinning drug, clopidogrel, due to a potential rebound effect that may be caused by increased activation of blood platelets (cells involved in blood clotting). A new study has found a twofold increase in the risk of death or heart attack in the first 90 days after acute coronary syndrome patients stopped taking clopidogrel compared with later time intervals (91-360 days) and compared with patients remaining on clopidogrel therapy. It also demonstrated that the adverse outcomes occurred across multiple patient groups: women vs. men, percutaneous coronary intervention vs. medical therapy without stents, drug-eluting stents vs. bare metal stents, and duration of clopidogrel treatment before cessation (>6 months vs. <6 months).

The study also highlighted the incidence of bleeding events around the time of clopidogrel cessation (~7 percent) and showed that the clustering of adverse events was specific to clopidogrel discontinuation. The fact that there was a clustering of adverse events after stopping clopidogrel but not after stopping an angiotensin converting enzyme inhibitor medication (while staying on clopidogrel) suggests that the clustering of events is not a general effect of stopping medications, note the researchers.

Their findings suggest an urgent need to develop strategies to attenuate the observed clustering of events after the end of a prescribed clopidogrel treatment course. The study population included 1,656 patients with postacute coronary syndrome patients who stopped clopidogrel and had been event-free before stopping the drug. This study was funded by the Agency for Healthcare Research and Quality (Contract No. 290-05-0033).

Patients suffering from a blockage in their coronary arteries usually undergo coronary angioplasty. In this procedure, a balloon-tipped catheter is inserted through the groin into the blocked artery along with a drug-eluting stent (wire mesh tube), which expands when the balloon is inflated to provide a scaffold to keep the coronary artery open. The stent remains once the balloon catheter is withdrawn. After this procedure, patients may be placed on clopidogrel, a blood-thinning agent, to prevent clots from forming on the stent. However, a new study finds that patients placed on clopidogrel have an increased risk of bleeding, although their risk for a heart attack decreases.

A total of 7,689 patients were evaluated for this study. All had received drug-eluting stents, with just under half (49.1 percent) receiving clopidogrel for more than 6 months. Patients were followed for up to 18 months for signs of major bleeding, a heart attack, or death. Particular attention was paid to the time interval from 0 to 6 months, the recommended time for clopidogrel therapy from the drug's manufacturer. After a mean follow-up of 418 days, 3.6 percent of patients experienced a major bleeding event. The percentage of patients who suffered a heart attack or died was 3.7 percent and 2.9 percent, respectively. Even when the researchers adjusted for various factors, there was still a significant association between clopidogrel and an increase in major bleeding for all time intervals. These included 0 to 6 months, 7 to 12 months, and 13 to 18 months. However, patients on clopidogrel had a decreased risk of having a heart attack for all time intervals while on the therapy. There was also a decrease in death rate for clopidogrel patients during the 7- to 12-month time interval.

The researchers call for more randomized clinical trials to determine the optimal time patients should be on clopidogrel in order to reduce bleeding risks and increase the benefits of therapy. The study was supported in part by the Agency for Healthcare Research and Quality (HS00331).

From the Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD (C.N.R.); and the Department of Human Genetics, University of Utah Health Sciences Center, Salt Lake City (L.B.J.).

Address reprint requests to Dr. Rotimi at the National Institutes of Health Center for Research on Genomics and Global Health, 12 South Dr., MSC 5635, Bethesda, MD 20851-5635, or at rotimic@mail.nih.gov.

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

BACKGROUND: Data on the association between sex hormone receptor polymorphisms and migraine are conflicting.

METHODS: We performed a systematic review and meta-analysis on this topic searching for studies published until August 2009. For each study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs.

RESULTS AND CONCLUSION: Among the seven genes targeted, four variants were investigated in multiple studies. Effect estimates from an additive model suggest that the ESR-1 594 G>A (pooled OR 1.37; 95% CI 1.02-1.83) and ESR-1 325 C>G (pooled OR 1.16; 95% CI 1.03-1.32) variants are associated with any migraine. This pattern does not differ between migraine with and without aura. In contrast, the ESR-1 Pvu II C>T and PGR PROGINS insert polymorphism do not appear to be associated with migraine. Results were driven by studies among Caucasians and may differ in other ethnic groups.

Evaluation of: The International Multiple Sclerosis Genetics Consortium (IMSGC). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes Immun. 11(5), 397-405 (2010). Multiple sclerosis (MS) develops in genetically susceptible populations as a result of environmental exposures, and discovering these genetic and/or environmental factors will provide fundamental new insights into the pathogenesis, diagnosis and treatment of this disabling disease. With the introduction of genome-wide association studies, the number of genes found to be associated with MS has increased rapidly. In all of these genes, in a study by the International Multiple Sclerosis Genetics Consortium, the classic MS risk locus, HLA-DRB1, stood out with remarkably strong statistical significance, but they also identified 12 other loci and/or genes associated with MS. However, all of these alleles have a very modest odds ratio and they explain approximately 3% of the variance in MS risk. Recently, the International Multiple Sclerosis Genetics Consortium provided evidence for three new loci that show significant association at a genome-wide level: RGS1, IL12A and MPHOSPH9/CDK2AP1. In this article, we will review the three newly discovered susceptibility loci and the implications of genome-wide association studies in MS on clinical practice.

BACKGROUND AND METHODS: Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published up to September 2009. For each study with genotype information, we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs.

RESULTS: Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR=2.02; 95% CI 1.24-3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR=1.41; 95% CI 0.83-2.40).

CONCLUSIONS: While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans.

Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America.

Abstract

This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host.

The role of apolipoprotein E (apo E) in lipid metabolism and cholesterol transport is well established. About 14 per cent of the variation in plasma cholesterol levels is attributed to polymorphisms in APO E gene (APO E). APO E consists of three common alleles, designated as ε2, ε3 and ε4 which code for E2, E3 and E4 proteins respectively resulting in three homozygous (E2/E2, E3/E3, E4/E4) and three heterozygous (E3/E2, E4/E2 and E4/E3) phenotypes. Different populations studied worldwide inherit variable frequencies of the APO E alleles and genotypes, with the most frequent allele being ε3.The ε4 allele has been consistently shown to be associated with Alzheimer's disease, coronary heart disease and cerebrovascular disorders. In this review, we have discussed the role of APO E polymorphisms in cerebrovascular and coronary heart diseases. The status of APO E polymorphisms and their disease associations in Asian Indians besides, other populations has also been discussed. Further, studies elucidating the pathophysiology of apo E deficiency conducted in knock-out mice have been reviewed.

BACKGROUND: Comparison of patients with coronary heart disease and controls in genome-wide association studies has revealed several single nucleotide polymorphisms (SNPs) associated with coronary heart disease. We aimed to establish the external validity of these findings and to obtain more precise risk estimates using a prospective cohort design.

METHODS: We tested 13 recently discovered SNPs for association with coronary heart disease in a case-control design including participants differing from those in the discovery samples (3829 participants with prevalent coronary heart disease and 48,897 controls free of the disease) and a prospective cohort design including 30,725 participants free of cardiovascular disease from Finland and Sweden. We modelled the 13 SNPs as a multilocus genetic risk score and used Cox proportional hazards models to estimate the association of genetic risk score with incident coronary heart disease. For case-control analyses we analysed associations between individual SNPs and quintiles of genetic risk score using logistic regression.

FINDINGS: In prospective cohort analyses, 1264 participants had a first coronary heart disease event during a median 10·7 years' follow-up (IQR 6·7-13·6). Genetic risk score was associated with a first coronary heart disease event. When compared with the bottom quintile of genetic risk score, participants in the top quintile were at 1·66-times increased risk of coronary heart disease in a model adjusting for traditional risk factors (95% CI 1·35-2·04, p value for linear trend=7·3×10(-10)). Adjustment for family history did not change these estimates. Genetic risk score did not improve C index over traditional risk factors and family history (p=0·19), nor did it have a significant effect on net reclassification improvement (2·2%, p=0·18); however, it did have a small effect on integrated discrimination index (0·004, p=0·0006). Results of the case-control analyses were similar to those of the prospective cohort analyses.

INTERPRETATION: Using a genetic risk score based on 13 SNPs associated with coronary heart disease, we can identify the 20% of individuals of European ancestry who are at roughly 70% increased risk of a first coronary heart disease event. The potential clinical use of this panel of SNPs remains to be defined.

BACKGROUND: Women who have inherited mutations in the BRCA1 or BRCA2 genes have substantially elevated risks of breast and ovarian cancer. Mutation carriers have various options, including extensive and regular surveillance, chemoprevention and risk-reducing surgery. The aim of this review is to provide an up-to-date analysis and to subsequently summarise the available literature in relation to risk-reducing strategies, with a keen focus on prophylactic surgery.

METHODS: The literature review is facilitated by Medline and PubMed databases. The cross-referencing of the obtained articles was used to identify other relevant studies.

RESULTS: Prophylactic surgery (bilateral mastectomy, bilateral salpingo-oophorectomy or a combination of both procedures) has proved to be the most effective risk-reducing strategy. There are no randomised controlled trials able to demonstrate the potential benefits or harms of prophylactic surgery; therefore, the evidence has been derived from retrospective and short follow-up prospective studies, in addition to hypothetical mathematical models. Based on the current knowledge, it is reasonable to recommend prophylactic oophorectomy for BRCA1 or BRCA2 mutation carriers when childbearing is completed in order to reduce the risk of developing breast and ovarian cancer. In addition, women should be offered the options of rigorous breast surveillance, chemoprevention with anti-oestrogens--especially for carriers of BRCA2--or bilateral prophylactic mastectomy.

CONCLUSION: The selection of the most appropriate risk-reducing strategy is not a straightforward task. The impact of risk-reducing strategies on cancer risk, survival, and overall quality of life are the key criteria considered for decision-making. Notably, various other factors should be taken into consideration when evaluating individual mutation carriers' individual circumstances, namely woman's age, morbidity, type of mutation, and individual preferences and expectations. Although prospective randomised controlled trials concerned with examining the various interventions in relation to the woman's age and type of mutation are needed, randomisation is extremely difficult and rather deemed unethical given the current available evidence from retrospective studies.

BACKGROUND: Bilateral mastectomy in women diagnosed with unilateral breast cancer is on the rise in the USA. One contributing factor is increased awareness of contralateral breast cancer risk. Positive testing for deleterious mutation in BRCA1/2 is a concrete measure of this contributing factor. We hypothesize that breast cancer surgery trend change is temporally associated with the introduction of BRCA1/2 genetic testing around 1996.

METHODS: Our study cohort included 158 BRCA1 or BRCA2 mutation carriers diagnosed with unilateral breast cancer between 1963 and 2009. Mutation carriers with ovarian cancer or bilateral breast cancer were excluded. Breast surgery and breast reconstruction surgery trends were analyzed according to year of breast cancer diagnosis or when bilateral mastectomy was performed, respectively.

RESULTS: Surgery trends changed significantly over time. We observed a significant drop in the rate of unilateral mastectomy (P < 0.001) after the period 1996-2000, and the rate of bilateral mastectomy appears to be on the rise, up to 30.3% between 2006 and 2009. Breast reconstruction trends also changed significantly over time, with a significant rise in the rate of free flap reconstruction to 58.8% between 2006 and 2009.

CONCLUSIONS: Our results demonstrated a significant decrease in unilateral mastectomy with a rise in bilateral mastectomy after the period 1996-2000, a period which encompassed the year when genetic testing of the two BRCA1/2 genes became commercially available, hence supporting our hypothesis.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10(-12)) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10(-11)) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10(-7)) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10(-11)) and a tag SNP for NAT2 acetylation status (P = 4 × 10(-11)), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.